Rituximab (RTX) and other anti-CD20 antibodies (ofatumumab and obinutuzumab (OBN)) dramatically improved treatment of Non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Alone or in combination with chemotherapy (e.g. R-CHOP, a combination with cyclophosphamide, doxorubicin, vincristine, and prednisone) they produced better clinical outcomes. However, relapses frequently occur with poor patient outcomes. In 2017 in the USA, there were an estimated 72,240 new cases of NHL and 20,140 deaths, 20,110 new cased of CLL and 4,660 deaths in both males and females. This demonstrates the need for improved treatment strategies. The goal of the proposed studies is to design, synthesize, and evaluate the second generation of drug-free macromolecular therapeutics (DFMT) for the treatment of B-cell malignancies. Anti-CD20 antibodies are divided into Type I such as RTX and Type II such as OBN; they have different patterns of binding to CD20 receptor. RTX binds between CD20 tetramers resulting in accumulation in lipid rafts, calcium influx and caspase activation. OBN binds within one tetramer with the conformation compatible with homotypic adhesion regions, leading to actin cytoskeleton remodeling and lysosome disruption. Our design enhances the activity of Type II OBN by triggering the apoptosis activation pathways of both types of antibodies. This new system is composed of two nanoconjugates: a) bispecific engager, OBN-MORF1 (OBN conjugated to one morpholino oligonucleotide MORF1); and b) a crosslinking (effector) component HSA- (MORF2)X (human serum albumin (HSA) grafted with multiple copies of complementary morpholino oligonucleotide 2). Modification of OBN with one MORF1 does not impact the binding of OBN-MORF1 to CD20 and following binding to CD20 Type II effects occur. Further exposure to multivalent effector HSA- (MORF2)X results in clustering the OBN-MORF1-CD20 complexes into lipid rafts and Type I effects occur. This new approach, called ?clustered OBN (cOBN)? combines effects of both antibody types resulting in very high apoptotic levels. In the bispecific engager, MORF1 will be attached to OBN via thioether bond following reduction of OBN's disulfide bonds. The structure of the multivalent crosslinking effector HSA-(MORF2)x will be optimized to ensure the highest efficiency of the cOBN system on disseminated models of NHL. Recently, combination of OBN with chlorambucil was FDA approved. We have shown that HSA-based DFMT sensitizes NHL cells to different chemotherapeutic agents. Thus we plan to evaluate the impact of combining cOBN with chemotherapeutics on the mechanism and efficiency of apoptosis induction. Finally, we demonstrated efficacy of DFMT on resistant lymphomas and cells isolated from patients diagnosed with various subtypes of B cell malignancies. We shall identify subsets of patients that respond favorably to our new therapeutics. In summary, this proposal is scientifically novel and has great translational potential. Also, it provides a new paradigm for the design of macromolecular therapeutics applicable to other diseases beyond lymphomas.